Immunostimulatory CpG on Carbon Nanotubes Selectively Inhibits Migration of Brain Tumor Cells

Abstract

Even when treated with aggressive current therapies, patients with glioblastoma usually survive less than two years and exhibit a high rate of recurrence. CpG is an oligonucleotide that activates the innate immune system via Toll-like receptor 9 (TLR9) activation. Injection of CpG into glioblastoma tumors showed promise as an immunotherapy in mouse models but proved disappointing in human trials. One aspect of glioma that is not addressed by CpG therapy alone is the highly invasive nature of glioma cells, which is associated with resistance to radiation and chemotherapy. Here, we demonstrate that single-walled carbon nanotubes noncovalently functionalized with CpG (SWNT/CpG), which retain the immunostimulatory property of the CpG, selectively inhibit the migration of glioma cells and not macrophages without affecting cell viability or proliferation. SWNT/CpG also selectively decreased NF-κB activation in glioma cells, while activating macrophages by induction of the TLR9/NF-κB pathway, as we have previously reported. The migration inhibition of glioma cells was correlated with selective reduction of intracellular levels of reactive oxygen species (ROS), suggesting that an antioxidant-based mechanism mediates the observed effects. To the best of our knowledge, SWNT/CpG is the first nanomaterial that inhibits the migration of cancer cells while stimulating the immune system.

Nanoscale Drug Delivery Systems in Glioblastoma

“…Although immunostimulatory oligonucleotide CpG was considered to activate TLR9 as well as initiate immune system to counteract GBM, its efficiency was proved disappointed in vivo. Darya et al [ 25 ] integrated CpG with SWCNT non-covalently, which assisted the delivery of CpG without affecting its therapeutic properties. They demonstrated that SWCNT/CpG inhibited the migration of GBM cells by inducing TLR9/ NF-κB pathway of macrophages.…”

Engineering Gene Therapy: Advances and Barriers

“…[ 417–419 ] Therefore, CpG‐ODNs‐based cancer therapies require careful consideration, as the stimulation of TLR9 receptor in some tumor cells could promote tumors growth and/or metastasis. [ 420,421 ] Optimizing the delivery systems and backbone modifications, partly overcome these limitations. Phosphorothioate modification of CpG‐ODN backbone, improve stability, and avoid DNases‐mediated degradation.…”

Materials Chemistry of Fullerenes, Graphenes, and Carbon Nanotubes

“…The co-delivery of a cytotoxic agent (doxorubicin-DOX) and a P-gp inhibitor (verapamil-VER) by oxMWCNT, resulted in a significant improvement in the DOX anticancer efficiency due to the increased drug uptake by leukemia drug-resistant cells [143]. The hybridization of CpG oligonucleotide onto pristine SWCNT was used as a strategy to enhance the cell internalization and thus the activation of the innate immune system via Toll-like receptor 9 in a malignant brain cancer model [144]. As a consequence, a selective inhibition of glioma cells migration was observed, while macrophages viability and proliferation remained almost unaltered.…”